The failure of adult CNS axons to sprout and to grow after injury limits recovery in a broad range of neurological conditions, including spinal cord injury (SCI), stroke, head trauma and chronic multiple sclerosis. Over the last 5 years, significant progress has been achieved towards defining the molecular pathways limiting adult CNS axon growth and towards translating this knowledge into therapeutic opportunities. During the last cycle of this project, we identified the Nogo-66 Receptor (NgR) protein as a ligand-binding receptor for the myelin-derived proteins, Nogo and MAG. Pharmacological perturbation of NgR function or genetic disruption of the NgR locus allows an enhanced degree of axonal growth for certain fibers in the post-SCI and post-stroke nervous system. We showed that such CNS fiber growth is associated with improved behavioral recovery of motor function. Success in promoting recovery from injury led us to consider of the physiological rather than pathological role of myelin inhibitors. We found that experience-dependent cortical plasticity is gated by NgR-dependent mechanisms in the absence of injury. While this work has defined one pathway regulating adult CNS axonal sprouting, it has also framed crucial questions about NgR function that will be addressed in the second cycle of this project. In the proposed work, we will examine the anatomical, molecular and temporal specificity of NgR action in plasticity and regeneration. We will consider the cellular basis for NgR-gated brain plasticity. The current hypothesis is that NgR functions to "lock" neuronal elements into place and to prevent anatomical rearrangements. The molecular basis for NgR signal transduction will also be probed biochemically and genetically. Together, these studies should provide critical insights into the mechanism and extent of NgR contribution to axonal plasticity and regeneration in the adult CNS. Such data will inform our understanding of the stability of connectivity within the CNS and illuminate the possibility of harnessing this knowledge for therapeutic interventions.